Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Nordic Group B.V., Siriusdreef 22, 2132 WT Hoofddorp, The Netherlands
This product SHOULD NEVER be prescribed in the following situations.
In all indications:
In the indication: medical termination of developing pregnancy:
In the indication: softening and dilatation of the cervix uteri prior to surgical termination of pregnancy:
In the indication: preparation for the action of prostaglandin analogues in the termination of pregnancy for medical reasons (beyond the first trimester):
Because of its abortifacient properties, mifepristone should never be used in a woman with an ongoing pregnancy who wants to complete it.
The age of the pregnancy must be determined from the questioning and the clinical examination of the patient. Uterine ultrasound is recommended.
In the absence of specific studies, mifepristone is not recommended in patients with:
This method requires an active involvement of the woman who should be informed of the method’s requirements:
In the case of a pregnancy occurring with an intra-uterine device in situ, this device must be removed before administration of mifepristone.
Failures:
The non-negligible risk of failure, which occurs in 1.3 to 7.5 % of the cases, makes the control visit mandatory in order to check that the expulsion is completed.
In rare case of non complete expulsion, a surgical revision may be necessary.
The efficacy of method decreases with parity, and consequently increasing age of the woman.
Bleeding:
The patient must be informed of the occurrence of prolonged vaginal bleeding (an average of about 12 days or more after mifepristone intake) which may be heavy. Bleeding occurs in almost all cases and is not in anyway a proof of complete expulsion.
The bleeding can occur very quickly after misoprostol intake, and sometimes later:
Rarely the expulsion may occur before administration of the prostaglandin analogue (around 3% of the cases). This does not preclude the control visit in order to check for the complete expulsion and the uterine vacuity.
The patient should be informed not to travel far away from the prescribing centre as long as complete expulsion has not been recorded. She will receive precise instructions as to whom she should contact and where to go, in the event of any problems emerging, particularly in the case of very heavy vaginal bleeding. This is bleeding that lasts longer than 12 days and/or that is heavier than the normal menstrual bleeding.
A follow-up visit must take place within a period of 14 to 21 days after the intake of mifepristone to verify by the appropriate means (clinical examination, together with beta-hCG measurement or ultrasound scan) that expulsion has been completed and that vaginal bleeding has stopped. In case of persistent bleeding (even light) beyond the control visit, its disappearance should be checked within a few days.
If an ongoing pregnancy is suspected, a further ultrasound scan may be required.
Persistence of vaginal bleeding at this point could signify incomplete abortion, or an undiagnosed ectopic pregnancy, and appropriate treatment should be considered.
Since heavy bleeding requiring haemostatic curettage occurs in 0 to 1.4% of the cases during the medical method of pregnancy termination, special care should be given to patients with haemostatic disorders with hypocoagulability, or with anaemia. The decision to use the medical or the surgical method should be decided with specialised consultants according to the type of haemostatic disorder and the level of anaemia.
In the event of an ongoing pregnancy diagnosed after the follow-up visit, termination by another method will be proposed to the woman.
Infection:
Serious cases (including fatal cases) of toxic shock and septic shock following infection with atypical pathogens (Clostridium sordellii or Escherichia coli) have been reported after medical abortion with the use of mifepristone 200 mg followed by unauthorised vaginal or buccal administration of misoprostol tablets.
Clinicians should be aware of this potentially fatal complication.
For the full efficacy of therapy, the use of Mifegyne must be followed, 36 to 48 hours later and not beyond, by surgical termination.
Bleeding:
The woman will be informed of the risk of vaginal bleeding which may be heavy, following intake of Mifegyne. She should be informed of the risk of abortion prior to surgery (although minimal). She will be informed on where to go in order to check for the completeness of expulsion, or in any case of emergency.
Since heavy bleeding requiring curettage occurs in about 1% of patients, special care should be given to patients with haemostatic disorders, hypocoagulability, or severe anaemia.
Other risks:
They are those of the surgical procedure.
In case of suspected acute adrenal failure, dexamethasone administration is recommended. 1 mg of dexamethasone antagonises a dose of 400 mg of mifepristone.
Due to the antiglucocorticoid activity of mifepristone, the efficacy of long-term corticosteroid therapy, including inhaled corticosteroids in asthmatic patients, may be decreased during the 3 to 4 days following intake of Mifegyne. Therapy should be adjusted.
The medical termination of pregnancy requires rhesus determination and hence the prevention of rhesus allo- immunisation as well as other general measures usually taken during any termination of pregnancy.
During clinical trials, pregnancies occurred between embryo expulsion and the resumption of menses. Therefore, when a termination of pregnancy conducted by medical procedure is medically confirmed, it is recommended to start contraception immediately.
The precautions related to prostaglandin analogues should also be followed.
Rare but serious cardiovascular accidents (myocardial infarction and/or spasm of the coronary arteries and severe hypotension) have been reported following the intra vaginal and intra muscular administration of a high dose of prostaglandin analogue. Misoprostol administered orally could also constitute a potential risk factor of acute cardiovascular events. For this reason, women with risk factors for cardiovascular disease (e.g. age over 35 years with chronic smoking, hyperlipidemia, diabetes) or established cardiovascular disease should be treated with caution.
The precautions related to the prostaglandin used should be followed where relevant.
During intake and for three hours following the intake, the patient should, in principle, be monitored in the treatment centre, in order not to miss possible acute effects of prostaglandin administration. The treatment centre must be equipped with adequate medical facilities.
On discharge from the treatment centre all women should be provided with appropriate medications as necessary and be fully counselled regarding the likely signs and symptoms she may experience and have direct access to the treatment centre by telephone or local access.
No interaction studies have been performed. On the basis of this drug’s metabolism by CYP3A4, it is possible that ketoconazole, itraconazole, erythromycin, and grapefruit juice may inhibit its metabolism (increasing serum levels of mifepristone). Furthermore, rifampicin, dexamethasone, St. John’s Wort and certain anticonvulsants (phenytoin, phenobarbital, carbamazepine) may induce mifepristone metabolism (lowering serum levels of mifepristone).
Based on in vitro inhibition information, co-administration of mifepristone may lead to an increase in serum levels of drugs that are CYP3A4 substrates. Due to the slow elimination of mifepristone from the body, such interaction may be observed for a prolonged period after its administration. Therefore, caution should be exercised when mifepristone is administered with drugs that are CYP3A4 substrates and have narrow therapeutic range, including some agents used during general anaesthesia.
A decrease of the efficacy of the method can theoretically occur due to the antiprostaglandin properties of non-steroidal anti-inflammatory drugs (NSAIDs) including aspirin (acetyl salicylic acid). Some evidence suggests that co-administration of NSAIDs on the day of prostaglandin administration does not adversely influence the effects of mifepristone or the prostaglandin on cervical ripening or uterine contractility and does not reduce the clinical efficacy of medical termination of pregnancy.
In animals (see section 5.3 Pre-clinical safety data), the abortifacient effect of mifepristone precludes the proper assessment of any teratogenic effect of the molecule.
With subabortive doses, malformations were observed in rabbits, but not in rats, mice or monkeys. In clinical practice, rare cases of malformations of the extremity of lower limbs (out of them, club-foot) have been reported in case of mifepristone administered alone or associated with prostaglandins. One of the possible mechanisms might be amniotic band syndrome. However, data is too limited to determine whether the molecule is a human teratogen.
Consequently:
Mifepristone is excreted in mother’s milk in small amounts. Consequently, mifepristone use should be avoided during breastfeeding.
Mifepristone does not affect fertility. It is possible that the woman becomes pregnant again as soon as the termination of pregnancy is completed. Therefore, it is important to inform the patient to start contraception immediately after the termination of the pregnancy is confirmed.
No data showing an effect on the ability to drive or using machines are known. Dizziness could occur as a side effect inherent of the abortion process. When driving or using machines one should take this possible side effect into account.
The frequencies of occurrence of side effects are classified as follows: Very common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1,000 to <1/100), Rare (≥1/10,000 to <1/1,000), Very rare (<1/10,000), Not known (cannot be estimated from the available data).
Common: Infection following abortion. Suspected or confirmed infections (endometritis, pelvic inflammatory disease) have been reported in less than 5% of women.
Very rare: Very rare cases of serious or fatal toxic and septic shock (caused by Clostridium sordellii or Escherichia coli), which can be with or without fever or other obvious symptoms of infection, have been reported after medical abortion with the use of unauthorised vaginal or buccal administration of misoprostol tablets for oral use. Clinicians should be aware of this potentially fatal complication (see section 4.4. – special warnings and special precautions for use).
Rare: Headache
Uncommon: Hypotension (0.25%)
Very common: Nausea, vomiting, diarrhoea (these gastro intestinal effects related to prostaglandin use are frequently reported).
Common: Cramping, light or moderate.
Uncommon: Hypersensitivity: Skin rashes uncommon (0.2%).
Rare: Single cases of urticaria, erythroderma, erythema nodosum, toxic epidermal necrolysis have also been reported.
Very rare: Angioedema
Very common: Very common uterine contractions or cramping (10 to 45%) in the hours following prostaglandin intake.
Common: Heavy bleeding occurs in about 5% of the cases and may require haemostatic curettage in up to 1.4% of the cases.
Rare: During induction of second trimester termination of pregnancy or labour induction for foetal death in utero within the third trimester, uterine rupture has been uncommonly reported after prostaglandin intake. The reports occurred particularly in multiparous women or in women with a caesarean section scar.
Rare: Malaise, vagal symptoms (hot flushes, dizziness, chills), fever.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
Not applicable.
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